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Immunoproteasome-selective and non-selective inhibitors: A promising approach for the treatment of multiple myeloma
Pharmacology & Therapeutics ( IF 12.0 ) Pub Date : 2017-09-11 , DOI: 10.1016/j.pharmthera.2017.09.001
Roberta Ettari , Maria Zappalà , Silvana Grasso , Caterina Musolino , Vanessa Innao , Alessandro Allegra

The ubiquitin-proteasome system (UPS) is the major non-lysosomal proteolytic system for the degradation of abnormal or damaged proteins no longer required. The proteasome is involved in degradation of numerous proteins which regulate the cell cycle, indicating a role in controlling cell proliferation and maintaining cell survival. Defects in the UPS can lead to anarchic cell proliferation and to tumor development.

For these reasons UPS inhibition has become a significant new strategy for drug development in cancer treatment.

In addition to the constitutive proteasome, which is expressed in all cells and tissues, higher organisms such as vertebrates possess two immune-type proteasomes, the thymoproteasome and the immunoproteasome. The thymoproteasome is specifically expressed by thymic cortical epithelial cells and has a role in positive selection of CD8 + T cells, whereas the immunoproteasome is predominantly expressed in monocytes and lymphocytes and is responsible for the generation of antigenic peptides for cell-mediated immunity. Recent studies demonstrated that the immunoproteasome has a preservative role during oxidative stress and is up-regulated in a number of pathological disorders including cancer, inflammatory and autoimmune diseases. As a consequence, immunoproteasome-selective inhibitors are currently the focus of anticancer drug design. At present, the commercially available proteasome inhibitors bortezomib and carfilzomib which have been validated in multiple myeloma and other model systems, appear to target both the constitutive and immunoproteasomes, indiscriminately. This lack of specificity may, in part, explain some of the side effects of these agents, such as peripheral neuropathy and gastrointestinal effects, which may be due to targeting of the constitutive proteasome in these tissues. In contrast, by selectively inhibiting the immunoproteasome, it may be possible to maintain the antimyeloma and antilymphoma efficacy while reducing these toxicities, thereby increasing the therapeutic index.

This review article will be focused on the discussion of the most promising immunoproteasome specific inhibitors which have been developed in recent years. Particular attention will be devoted to the description of their mechanism of action, their structure-activity relationship, and their potential application in therapy.



中文翻译:

免疫蛋白酶体选择性和非选择性抑制剂:治疗多发性骨髓瘤的一种有前途的方法

泛素-蛋白酶体系统(UPS)是主要的非溶酶体蛋白水解系统,用于降解不再需要的异常或受损蛋白质。蛋白酶体参与许多调节细胞周期的蛋白质的降解,表明其在控制细胞增殖和维持细胞存活中的作用。UPS中的缺陷可能导致无政府状态的细胞增殖并导致肿瘤发展。

由于这些原因,UPS抑制已成为癌症治疗中药物开发的重要新策略。

除了在所有细胞和组织中表达的组成型蛋白酶体之外,高等生物(如脊椎动物)还具有两种免疫型蛋白酶体,即胸腺蛋白酶体和免疫蛋白酶体。胸腺蛋白酶体由胸腺皮质上皮细胞特异性表达,并在CD8 + T细胞的阳性选择中发挥作用,而免疫蛋白酶体主要在单核细胞和淋巴细胞中表达,并负责产生抗原肽以用于细胞介导的免疫。最近的研究表明,免疫蛋白酶体在氧化应激过程中具有防腐作用,并在包括癌症,炎性疾病和自身免疫性疾病在内的许多病理疾病中被上调。结果,免疫蛋白酶体选择性抑制剂目前是抗癌药物设计的重点。目前,已经在多发性骨髓瘤和其他模型系统中验证的市售蛋白酶体抑制剂硼替佐米和卡非佐米似乎毫无区别地靶向组成型和免疫蛋白酶体。缺乏特异性可能部分解释了这些药物的某些副作用,例如周围神经病变和胃肠道副作用,这可能是由于在这些组织中靶向组成型蛋白酶体所致。相反,通过选择性抑制免疫蛋白酶体,可以维持抗骨髓瘤和抗淋巴瘤的功效,同时降低这些毒性,从而增加治疗指数。似乎不分青红皂白地靶向组成型和免疫蛋白酶体。缺乏特异性可能部分解释了这些药物的某些副作用,例如周围神经病变和胃肠道副作用,这可能是由于在这些组织中靶向组成型蛋白酶体所致。相反,通过选择性抑制免疫蛋白酶体,可以维持抗骨髓瘤和抗淋巴瘤的功效,同时降低这些毒性,从而增加治疗指数。似乎不分青红皂白地靶向组成型和免疫蛋白酶体。缺乏特异性可能部分解释了这些药物的某些副作用,例如周围神经病变和胃肠道副作用,这可能是由于在这些组织中靶向组成型蛋白酶体所致。相反,通过选择性抑制免疫蛋白酶体,可以维持抗骨髓瘤和抗淋巴瘤的功效,同时降低这些毒性,从而增加治疗指数。

这篇综述文章将重点讨论近年来已开发的最有希望的免疫蛋白酶体特异性抑制剂。将特别注意其作用机理,其结构-活性关系及其在治疗中的潜在应用的描述。

更新日期:2017-09-11
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